Derivation of occupational exposure levels (OELs) of Low-toxicity isometric biopersistent particles: how can the kinetic lung overload paradigm be used for improved inhalation toxicity study design and OEL-derivation?

Abstract

BackgroundConvincing evidence suggests that poorly soluble low-toxicity particles (PSP) exert two unifying major modes of action (MoA), in which one appears to be deposition-related acute, whilst the other is retention-related and occurs with particle accumulation in the lung and associated persistent inflammation. Either MoA has its study- and cumulative dose-specific adverse outcome and metric. Modeling procedures were applied to better understand as to which extent protocol variables may predetermine any specific outcome of study. The results from modeled and empirical studies served as basis to derive OELs from modeled and empirically confirmed directions.ResultsThis analysis demonstrates that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study design may not always be appropriate to unequivocally discriminate the surface thermodynamics-related acute adversity from the cumulative retention volume-related chronic adversity. Thus, in the absence of kinetically designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects.ConclusionIt is concluded that the degree of dissolution of particles in the pulmonary environment seems to be generally underestimated with the possibility to attribute to toxicity due to decreased particle size and associated changes in thermodynamics and kinetics of dissolution. Accordingly, acute deposition-related outcomes become an important secondary variable within the pulmonary microenvironment. In turn, lung-overload related chronic adversities seem to be better described by the particle volume metric. This analysis supports the concept that ‘self-validating’, hypothesis-based computational study design delivers the highest level of unifying information required for the risk characterization of PSP. In demonstrating that the PSP under consideration is truly following the generic PSP-paradigm, this higher level of mechanistic information reduces the potential uncertainty involved with OEL derivation.

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

“…It has also been suggested that due to the long retention times and associated bio-persistence of some materials in the lung, even short-term inhalation studies may require post-exposure periods of at least 3 months to reveal specific dispositional and toxicological characteristics. Therefore inhalation studies should be designed and executed with intermittent dosing and recovery periods to allow for the development of patterns in the accumulation and clearance at the portal of entry and manifestation of toxicity (Pauluhn, 2014). It is also important to state that the transport rate of materials, i.e.…”

“…In all reality, any potential pathogenic effects of inhaled NMs in the pulmonary system are dependent on a substantial lung burden which is determined by the site and extent of deposition in the lung and eventual clearance (Oakes et al 2013, Pauluhn, 2014. This deposition and clearance takes place throughout the respiratory tract and is heavily influenced by material size and surface properties (Muhlfeld et al 2008).…”

Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations

“…4) (Braakhuis et al, 2014;Pauluhn, 2011Pauluhn, , 2014. Pauluhn (2011) compared pulmonary toxicokinetics using data from rat inhalation bioassays of different types of PSPs including TiO 2 and concluded that PSP-related pulmonary toxicity was dependent on volume-based cumulative lung exposure dose.…”

“…This formula involved characterizing a volume concentration of respirable particulate, which the author defined as >1 ml/lung (~6% of the alveolar macrophage volume), in which recruitment of additional phagocytic and inflammatory cells occurs. According to Pauluhn, "adversities occurring beyond this overload-threshold may follow multiple and complex cumulative-dose-dependent Adverse Outcome Pathways (AOP)" (Pauluhn, 2014). …”

“…The MIE, which was hypothesized in the 1980s, is described to involve volumetric overload of alveolar macrophages as these cells engulf particulate matter (Morrow, 1992). Pauluhn (2014) has suggested that an increase in the "pool-size" of alveolar macrophages and neutrophilic granulocytes (PMN) represents an early homeostatic response to PSPs. Based on such, he previously developed a formula/model for predicting no effect levels of PSPs based on displacement volume of particulate within the available pool of alveolar macrophages (Pauluhn, 2011).…”